The focus of this component of the Alcohol Research Center is on acute functional tolerance. We now have lines of mice selectively bred for High Acute Functional Tolerance (LAFT1 and 2). These mice will be used to study the mechanisms of this acute tolerance and to define its relationship to other forms that are being studied in this component, ie, Very Rapid Acute Functional Tolerance (VRAFT) and Rapid Tolerance. Over components are investigating the mechanisms of chronic tolerance. By processes well established in this center we will correlate the various forms of tolerance with other behavioral aspects of ethanol's action such as sleep time, hypothermia, ethanol consumption, and locomotor activity. By utilizing the LS X SS recombinant inbred strains of mice, we have identified potential QTLs for AFT and will do the same for VRAFT. By selectively breeding for AFT we have generated lines of animals (HAFT and LAFT) from which QTLs can be determined for AFT as well as for VRAFT in F2 crosses of these lines. Other studies will investigate the neurochemical mechanisms responsible for these forms of tolerance. This will be accomplished by determining the specificity of AFT and VRAFT for ethanol by use of other CNS active drugs , specific for various receptor systems, and also investigate the ability of agonists and antagonists to influence development of AFT and VRAFT. Recent studies point to initial sensitivity and tolerance as important determinants of the risk of alcoholism in humans. These studies should provide a road map to studies in humans in these areas.